N-quinolinyl alkyl-substituted 1-aryloxy-2-propanolamine and propylamine derivatives possessing class III antiarrhythmic activity

ABSTRACT

This invention relates to N-heteroalkyl-substituted 1-aryloxy-2-propanolamine and propylamine derivatives possessing anti-arrhythmic activity, to pharmaceutical compositions and to methods for production thereof.

This is a continuation-in-part application of copending application U.S.Ser. No. 07/521,787, filed May 10, 1990 now abandoned, which is in turna continuation-in-part application of copending application U.S. Ser.No. 07/451,391, filed Dec. 11, 1989 now abandoned.

BACKGROUND OF THE INVENTION

Class III antiarrhythmic agents may be categorized as having the abilityto markedly prolong dog Purkinje fiber action potential duration withoutproducing significant changes in maximal upstroke velocity. Unlike ClassI anit-arrhythmic agents, a pure Class III agent displays no effect oncardiac sodium channels. The electrophysiologic properties of a compounddefining a Class III activity profile are observed in vivo as negligibleeffects on atrial, ventricular and H-V conduction lines while producinga marked increase (greater than 20 percent) in both the atrial andventricular refractory period. In contrast, Class I agents willdemonstrate a marked slowing of ventricular conduction velocity,generally without significant changes in the refractory period. Recentreviews of these agents are by: Bexton et al., Pharmac. Ther., 17,315-55 (1982); Vaughan-Williams, J. Clin. Pharmacol., 24, 129-47 (1984);and Steinberg et al., Ann. Rep. Med. Chem., 21, 95-108 (1986).

The following workers have reported the selective Class IIIantiarrhythmic activity of the dextro enantiomer of4-(2-isopropylamino-1-hydroxyethyl)-methanesulfonamide (MJ-1999,Sotalol): Taggart et al., Clin. Sci., 69, 631-636 (1985) and McComb etal., J. Am. Coll. Cardiol., 5, 438 (1985).

Wohl et al., discloseN-[2-(diethylamino)ethyl]-4-[(methylsulfonyl)amino]-benzamidehydrochloride as a potential class III antiarrhythmic agent in U.S. Pat.No. 4,544,654, Oct. 1, 1985.

Cross et al., have recently reported various N-heterocycle methylsubstituted α-phenylethylamine derivatives as useful antiarrhythmicagents in European Patent 0281254, Sept. 7, 1988, as well as otheralkyl-sulfonamide compounds reported in European Patent 0286277 andEuropean Patent 0286278, Oct. 12, 1988. Almgren et al. have recentlyreported 4-cyano-phenyl ether derivatives as useful antiarrhythmicagents in European Patent 0322390, June 28, 1989.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a group ofantiarrhythmic agents classified by their pharmacological profile asClass III antiarrhythmic agents of the formula (I): ##STR1## wherein R¹is alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido of 6 to 10carbon atoms, perfluoroalkylsulfonamido of 1 to 6 carbon atoms,perfluoroalkylamido of 1 to 6 carbon atoms, alkylsulfone oralkylsulfoxide of 1 to 6 carbon atoms, NO₂, CN, or 1-imidazoyl; R² isstraight or branched alkyl chain of 1 to 6 carbon atoms; X is O, S, orNR³ wherein R³ is H or a straight or branched alkyl chain of 1 to 6carbon atoms; Y is CH₂ or CHOH; Het is selected from the groupconsisting of ##STR2## wherein R⁴ is H, --NHSO₂ (C₁ to C₆ alkyl),--NHCO(C₁ to C₆ alkyl), Cl, F, Br, OCH₃ or NO₂ ; and Z is O, S, or NR⁵wherein R⁵ is H, C₁ to C₆ alkyl or the alkylsulfonamido of 1 to 6 carbonatoms and the pharmaceutically acceptable salts thereof.

Examples of alkyl as a group or part of a group, e.g. alkylsulfonamido,are methyl, ethyl, propyl, isopropyl and butyl. Examples ofperfluoroalkyl are CF₃, C₂ F₅ and C₃ F₇. Examples of aryl are phenyl,naphth-1-yl and naphth-2-yl. Preferred values for R¹ are nitro andalkylsulfonamido such as methylsulfonamido. Preferably X is O. Preferredvalues of Het are ##STR3##

Preferably R⁴ is hydrogen, Cl, F, OCH₃ or alkylsulfonamido, e.g.methylsulfonamido.

A further preferred aspect of the present invention are the compounds

N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamide;

N-[2-[[[2-hydroxy-3-[4-[(methylsulfonyl)amino]phenoxy]propyl]methyl]amino]methyl]-6-quinolinyl]methanesulfonamide;

N-[4-[3-[[(6-fluoro-2-quinolinyl)methyl]methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide;

N-[4-[3-[[(6-chloro-2-quinolinyl)methyl]methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide;

N-[4-[2-hydroxy-3-[[(6-methoxy-2-quinolinyl)methyl]methylamino]propoxy]phenyl]methanesulfonamide;

N-[4-[3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamide;

N-[2-[[methyl[3-[4-[(methylsulfonyl)amino]phenoxy]propyl]amino]methyl]-6-quinolinyl]methanesulfonamide;

N-[4-[3-[methyl(2-quinoxalinylmethyl)amino]propoxy]phenyl]methanesulfonamide;

N-[4-[2-hydroxy-3-[methyl(2-quinoxalinylmethyl)amino]propoxy]phenyl]methanesulfonamide;

1-[(1H-benzimidazol-2-ylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanol;

N-[4-[3-[(1H-benzimidazol-2-ylmethyl)methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide;

1-[methyl(2-quinolinylmethyl)amino]-3-(4-nitrophenoxy)-2-propanol;

1-[(2-benzofuranylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanol;

(+)-(R)-N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamide;

(-)-(S)-N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamide;

N-[4-[3-[(2-benzofuranylmethyl)methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide;

1-[(2-benzoxazolylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanol;

and the pharmaceutically acceptable salts thereof.

It is to be understood that the definition of the compounds of formula(I) and (II) encompass all possible stereoisomers and mixtures thereofwhich possess the activity discussed below. In particular, itencompasses racemic modifications and any optical isomers which possessthe indicated activity.

Optical isomers may be obtained in pure form by standard separationtechniques. For example, a racemic mixture may be converted to a mixtureof optically active diastereoisomers by reaction with a singleenantiomer of a resolving agent, for example, by salt formation orformation of a covalent bond. The resulting mixture of optically activediastereoisomers may be separated by standard techniques (e.g.crystallization or chromatography) and individual optically activediastereoisomers then treated to remove the resolving agent therebyreleasing the single enantiomer of the compound of the invention. Chiralchromatography (using a chiral support, eluent or ion pairing agent) mayalso be used to separate enantiomeric mixtures directly.

Stereospecific synthesis using optically active starting materialsand/or chiral reagents or catalysts and/or solvents may also be employedto prepare a particular enantiomer.

For example, where the compound of formula (I) is prepared by anaddition process creating an optical center then carrying out thereaction using a chiral catalyst or agent or in a chiral environment cangive the product as a single enantiomer.

The pharmaceutically acceptable salts of the antiarrhythmic agents ofthis invention are prepared directly by neutralization of the free base.These physiologically acceptable salts may be formed with organic orinorganic acids, such as hydrochloric, hydrobromic, phosphoric,sulfuric, sulfamic, nitric, methylsulfonic, acetic, maleic, succinic,fumaric, tartaric, citric, salicylic, lactic, naphthalenesulfonic acidand the like.

This invention also provides processes for preparing the compounds offormula (I). More particularly, the compounds of formula (I) may beprepared by one of the following processes:

a) reacting a compound of formula ##STR4## wherein X and R¹ are asdefined above, with a compound of formula

    HN(R.sup.2)CH.sub.2 Het                                    (III)

wherein R² and Het are as defined above to give a compound of formula(I) wherein Y is CHOH; or

b) reacting a compound of formula ##STR5## wherein R¹ and X are asdefined above, with a compound of formula ##STR6## wherein R² and Hetare as defined above to give a compound of formula (I) wherein Y isCHOH; or

c) reacting a compound of formula ##STR7## wherein R¹ and X are asdefined above and L is a leaving group, e.g. a halide, or an aryl- oralkyl-sulphonyloxy group such as p-tolyl- or methane-sulphonyloxy, witha compound of formula (III) as defined above, to give a compound offormula (I) wherein Y is CH₂ ; or

d) reacting a compound of formula (IV) as defined above with a compoundof formula ##STR8## wherein R², Het and L are as defined above to give acompound of formula (I) wherein Y is CH₂ ; or

e) reacting a compound of formula ##STR9## wherein R¹, X and R² are asdefined above with

A) a compound of formula

    L--CH.sub.2 --Het                                          (IX)

or

B) a compound of formula

    O═CH--Het                                              (X)

wherein L and Het are as defined above, the reaction being carried outunder reductive amination conditions when the compound of formula (X) isused, to give a compound of formula (I); or

f) reducing a compound of formula ##STR10## wherein X, Y, R¹, R² and Hetare as defined above to give a compound of formula (I); or

g) reductively aminating a compound of formula ##STR11## wherein R¹, X,Y and Het are as defined above, with an aldehyde of formula R³ CHOwherein R³ represents hydrogen or alkyl of 1 to 5 carbon atoms; or

h) acylating a compound of formula (I) wherein R¹ is amino to give acorresponding compound of formula (I) wherein R¹ is an alkyl-, aryl- orperfluoroalkyl-sulfonamido group or a perfluoroalkylamido group; or

i) acidifying a compound of formula (I) to give an acid addition salt orneutralizing an acid addition salt of a compound of formula (I) to givethe free base.

With regard to processes a) and b) the reaction may be convenientlycarried out at room temperature or with heating in a polar inert solventsuch as an alcohol, acetone or acetonitrile.

With regard to processes c), d) and e) A) the reaction may be carriedout in the presence of a suitable base such as diisopropylamine,triethylamine or an alkali metal carbonate or bicarbonate in an inertpolar solvent.

With regard to processes e) B) and g) the reductive amination may beeffected using hydrogen in the presence of a suitable catalyst such aspalladium on carbon or sodium cyanoborohydride according to standardprocedures, e.g. using an alcohol solvent.

Process f) may be conveniently carried out using a reducing agent suchas diborane or lithium aluminiumhydride in an inert solvent.

Process h) may be carried out under standard acylation proceduresoptionally in the presence of a base.

These reactants are generally known compounds or otherwise are routinelyprepared by techniques well within the skill of the chemist.

The compounds of this invention demonstrate antiarrhythmic activity whentested in the standard experimental animal in accordance with thefollowing procedure.

VENTRICULAR FIBRILLATION THRESHOLD

Mongrel dogs of both sexes weighing 12 to 18 kg were anesthetized withsodium pentobarbital (35 mg/kg i.v. supplemented with 5 mg/kg/h) andartificially ventilated with room air (minute volume: 200 mL/kg).

A right thoracotomy was performed at the fifth intercostal space and theheart suspended in a pericardial cradle. Bipolar electrodes forstimulation were sutured to the free wall of the right atrium and to theright ventricle.

Arterial blood pressure and lead II ECG were displayed on a chartrecorder and monitored on an oscilloscope. The dog heart was paced by astimulus for driving a constant current isolation unit.

Ventricular fibrillation threshold (VFT) was determined during atrialpacing at 2.5 Hg. Trains of 4-msec duration square-wave pulses (50 Hz,200-msec duration) were delivered to the right ventricle via theepicardial bipolar electrode (silver contacts 1 mm in diameter and 5 mmapart embedded in acrylic matrix). Trains of pulses were delivered every12th paced beat and were timed to terminate with the end of the T waveof the ECG. Current intensity was increased progressively untilventricular fibrillation (VF) occurred. The lowest current intensityproducing VF was defined as the ventricular fibrillation threshold(VFT). When fibrillation occurred the heart was defibrillated within 10seconds from the onset of fibrillation using a defibrillator charged to10 J. After defibrillation the animal was allowed to recover for atleast 30 minutes or until the ECG returned to normal. VFT was measuredtwice before drug administration to establish a stable pre-drugthreshold.

Dogs were randomized to receive either test drug or vehicle by i.v.route. Animals treated with vehicle do not show any significant increaseof VFT. The ability of test agents to elevate the threshold generally isaccepted as an indication of potential antifibrillary activity, asvehicle-treated animals on repeated trials do not show any appreciableincrease of VFT. This conclusion is supported by the observation that asubstantial fraction of the animals treated with the test drugspontaneously defibrillate and return to sinus rhythm. Spontaneouslydefibrillation of vehicle treated animals is an exceedingly rarephenomenon.

    ______________________________________                                        Ventricular Fibrillation Threshold in Dog (n = 6; x + S.E.)                                   Cmpd 4                                                        Pre-Drug Vehicle                                                                              (5 mg/kg)                                                     ______________________________________                                        8 + 2*          25 + 7.sup.•                                            ______________________________________                                         *Current threshold in mA necessary to induce fibrillation.                    .sup.• 2 to the 6 animals defibrillated spontaneously              

CARDIAC ELECTROPHYSIOLOGY

The compounds of this invention display a Class III antiarrhythmicprofile. The Class III antiarrhythmic activity was established in vitroand in vivo in accordance with the following standard test procedures:

IN VITRO

Bundles of free-running Purkinje fibers with attached myocardiumobtained from either ventricle of adult dog heart were pinned withoutstretching to the bottom of a 10 mL tissue chamber and continuouslysuperfused with oxygenated Tyrode's solution at a flow rate of 5mL/minute. The composition of the Tyrode's solution was (mM): NaCl, 138;KCl 4; CaCl₂, 2; MgCl₂, 0.5; NaHCO₃, 24; dextrose, 5.5. The solution wasaerated with 95% O₂ --5% CO₂ at 37° C. Bath temperature was maintainedat 37°±0.5° C. by circulating the pre-warmed superfusate through athermostatically controlled water bath immediately prior to entering thetissue chamber.

The preparations were stimulated through bipolar Teflon-coated silverwires, bared at the tips, placed on the endocardial surface of theattached myocardium, using a digital stimulator set to deliver constantcurrent pulses 1.5-msec in duration at cycle lengths of 300 or 1000msec. Stimulus strength was set at approximately 2×diastolic threshold,and adjusted as required throughout the experiment. All preparationswere allowed to equilibrate in the tissue chamber for at least 1 hourbefore measurements were begun. Subsequently, a minimum of 60 minuteswere allowed for equilibration with each drug-containing superfusatebefore post-drug measurements were made. Impalements were made at 6 to10 sites throughout the preparation before and after drug exposure.Offset potentials were rechecked after each impalement.

Glass microelectrodes filled with 3M KCl were coupled to high impedancenegative capacitance electrometers and Ag/AgCl half-cells used asreference electrodes. The first derivative of the action potentialupstroke (V_(max)) was obtained using an analog differentiator circuit,coupled to a peak-hold circuit that retained the recorded value ofV_(max) for 30 to 70-msec. Action potential and V_(max) tracings weredisplayed on a storage oscilloscope, and photographed for lateranalysis. In addition, chart paper recordings of V_(max) were obtainedusing the peak-hold device output.

Fresh stock solutions of drug were prepared for each experiment.Compounds were dissolved in distilled water at total concentrations of 1to 10 mg/mL, and subsequently diluted to a final concentration of 3 to10 μM in appropriate volumes of normal Tyrode's solution for evaluation.

Action potential (AP) parameters measured included: diastolic take-offpotential (or activation voltage, V.sub.(act) ; AP overshoot (V_(os));AP duration measured as the time taken to repolarize to -20 mV (APD₋₂₀),-60 mV (APD₋₆₀), and -80 mV (APD₋₈₀); and maximal upstroke velocity(V_(max)). An increase in APD₋₆₀ that occurred without a significantchange in V_(max) was taken, by definition, to indicate Class IIIantiarrhythmic activity "in vitro".

IN VIVO

Mongrel dogs of both sexes weighing 12 to 18 kg were anesthetized withsodium pentobarbital (35 mg/kg i.v. supplemented with 5 mg/kg/h) andartificially ventilated with room air (minute volume: 200 mL/kg).

The heart was exposed by a right thoractomy performed at the fifthintercostal space and suspended in a pericardial cradle. Epicardialelectrodes for stimulation and recording were sutured to the free wallof the lower right atrium and near the base of the right ventricle. Eachelectrode set contained a linear array of electrodes consisting of 1bipolar stimulating electrode and 2 bipolar recording electrodesembedded in a rigid acrylic matrix. The stimulating bipole was 7 mm fromthe proximal recording electrode, which in turn was 10 mm from thedistal recording bipole. Each electrode array was oriented to beparallel to the epicardial fiber axis.

Arterial blood pressure and lead II ECG were displayed on a chartrecorder and monitored on an oscilloscope. Conduction times andrefractory periods were measured during pacing at a cycle length of 300msec. The dog heart was paced by a stimulator driving a constant currentisolation unit. Electrical signals from the atrial and ventricularelectrodes were displayed on a digital oscilloscope and recorded by aink-jet recorder. Diastolic threshold was determined before and aftereach trial.

Refractory periods of the right atrium and right ventricle (AERP andVERP) were determined by introducing an extrastimulus (S₂) every 8 pacedbeats (S₁). The extrastimulus was followed by a 4-second rest intervalduring which no pacing occurred. Both S₁ and S₂ were of identicalintensity (twice threshold) and duration (2 msec). The S₁ -S₂ intervalwas gradually decreased in 2-msec steps until the extra-stimulus failedto induce a propagated response. This S₁ -S₂ interval was considered todefine effective refractory period.

Atrial and ventricular (ACT and VCT) conduction times were measured asthe time interval between the 2 electrograms recorded at the proximaland distal sites of the recording electrode array. The time ofactivation for electrograms with predominantly biphasic complexes wastaken as the moment when the trace crossed the zero reference line, andfor triphasic complexes, as the peak of the major deflection.

Animals received the test compound by i.v. injection. Drugs wereadministered cumulatively at the following dose levels: 1, 2.5, 5, 7.5,10 mg/kg. Each dose was administered over a 3 minute period.Electrophysiologic testing was performed 15 minutes following the end ofdosing. Every 30 minutes the dog received the next incremental dose.

Vehicle-treated animals did not show any significant change of theelectrophysiologic parameters. An increase in ERP that occurred withouta significant decrease of CT was taken, by definition to indicate "invivo" Class III antiarrhythmic activity.

The results of the assays are set forth in the table below:

    __________________________________________________________________________    Biological Data                                                               Purkinje Fiber 3 μM       Anesthetized Dog (5 mg/kg)                       BCL = 300        BCL = 1000  BCL = 300                                        Example                                                                            APD.sub.-60                                                                         V.sub.max                                                                           APD.sub.-60                                                                         V.sub.max                                                                           AERP VERP  ACT  VCT   HR     BP                  __________________________________________________________________________    1    71     1*               71   17    -4   -3    -24    -22                 .sup. 2ψ                                                                       61    7     38    9     41   18     26  -6    -20    -22                 3    (did not pace)                                                                            129   8     90   14    -5   -8    -25    -13                 7    18    2     32    15                                                     6    17    2     43    1     36   11    -8   -6     8      -8                 5     8    12    26    26    25   13    -7    0    -23      8                 4    27 ± 4                                                                           -9 ± 3                                                                           62 ± 10                                                                          -7 ± 6                                                                           51   27    -11   0    -22    -17                      (n = 3)                 (n = 2)         (n = 2)                          8    22    +3    45    5     52   30    -6    1    -21     -8                            (n = 2)                (n = 2)                                     9    27    -1    43    -4                                                     10   22    0     67    1     66   18    -7   -8    -38    -20                 11   22    9     55    11                                                     12   20    2     59    3                                                      13   10    1     31    +17                                                     14  21    -24   65    -17   53 ± 10                                                                         26 ± 3                                                                           -5 ± 1                                                                          -1 ± 3                                                                           -16 ± 8                                                                           4 ± 5                                         (n = 3)                                          15   22    7     40    -4                                                     __________________________________________________________________________     *Paced at 500 msec                                                            ψDosed at 10 mg/kg in anesthetized dog and at 10 μM in Purkinje        fiber                                                                          Dosed at 0.05 mg/kg in anesthetized dog and at 0.03 μM in Purkinje        fiber                                                                    

Based upon the activity profile elicited by the compounds of thisinvention in the above-described standard scientifically recognized testmodels, the compounds are established as antiarrhythmic agents useful inthe treatment of cardiac arrhythmia and conditions characterized bycoronary arteries vasospasm. For that purpose, the compounds may beadministered orally or parenterally in suitable dosage forms compatiblewith the route of administration, whether oral, intraperitoneal,intramuscular, intravenous, internasal, buccal, etc. The effective doserange determined in the animal test models has been established at fromabout 0.05 to about 5 milligrams per kilogram host body weight i.v., andfrom about 0.1 to about 5 mg/kg p.o., to be administered in single orplural doses as needed to relieve the arrhythmatic dysfunction. Thespecific dosage regimen for a given patient will depend upon age,pathological state, severity of dysfunction, size of the patient, etc.Oral administration is performed with either a liquid or solid dosageunit in any conventional form such as tablets, capsules, solutions,etc., which comprise a unit dose (e.g. from about 50 milligrams to about400 milligrams) of the active ingredient alone or in combination withadjuvants needed for conventional coating, tableting, solubilizing,flavoring or coloring. Parenteral administration with liquid unit dosageforms may be via sterile solutions or suspensions in aqueous oroleaginous medium. Isotonic aqueous vehicle for injection is preferredwith or without stabilizers, preservatives and emulsifiers.

The following examples illustrate the preparation of a representativenumber of compounds of this invention.

EXAMPLE 11-[(1H-Benzimidazol-2-ylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanolDihydrochloride Step 1) Preparation of 1-(4-Nitrophenoxy)-2,3-propene

To a solution of sodium 4-nitrophenoxide (30 g, 0.186 mol) in DMF (400mL) was added allyl bromide (24 mL, 0.28 mol). The reaction mixture wasstirred under a nitrogen atmosphere at room temperature for 48 hours,then diluted with water (300 mL) and extracted with ether (3×100 mL).The combined organic fraction was diluted with pentane until it becameturbid. It was then washed with water (2×100 mL), dried (MgSO₄), andconcentrated to afford 27.5 g of product (83%) as a red oil ofsufficient purity to use in the next step.

¹ H NMR (CDCl₃): δ8.19 (d, 2H, J=8 Hz, ArH), 6.97 (d, 2H, J=8 Hz, ArH),6.17 (m, 1H, --CH═CH₂), 5.40 (m, 2H, --CH═CH₂), 4.65 (d, 2H, J=6 Hz,O--CH₂ --).

Step 2) Preparation of 2-[(4-Nitrophenoxy)methyl]oxirane

To a solution of 1-(4-nitrophenoxy)-2,3-propene (19.25 g, 0.107 mol) indry methylene chloride (300 mL) was slowly added meta-chloroperbenzoicacid (24.13 g, 0.14 mol). The reaction mixture was stirred under anitrogen atmosphere for 48 hours. The mixture was filtered and thefiltrate was concentrated to afford a yellow residue. Trituration of theyellow residue with ether yielded the crude product as yellow crystals.Purification by flash chromatography afforded 11.75 g (56%) of productas a light yellow solid m.p. 63°-65° C.

¹ H NMR (CDCl₃): δ8.15 (d, J=8.2 Hz, 2 ArH), 6.95 (d,J=8.2 Hz, 2 ArH),4.36 and 3.98 (2m, --OCH₂ --CH), 3.36 (m, 1H, epoxide methine), 2.92 and2.76 (2m, 2H, epoxide methylene).

Anal. Calcd.: C, 59.19; H, 5.87; N, 6.27. Found: C, 59.51; H, 5.84; N,6.31.

Step 3) Preparation of 2-(Methylaminomethyl)benzimidazole

2-Chloromethylbenzimidazole (3.00 g, 18.01 mmol) was dissolved inaqueous methylamine (50 mL, 40 wt % in H₂ O) at 10° C. under N₂. After30 minutes, the reaction mixture was warmed to room temperature andstirred for 4 hours. Water was added and the mixture extracted withmethylene chloride. The organic phase was dried (MgSO₄) and concentratedto afford crude product which was purified by HPLC (gradientmethanol/dichloromethane) to afford 0.650 g (22%) of pure product as atan solid.

¹ H NMR (CDCl₃): δ7.56 (m, 2H, ArH), 7.22 (m, 2H, ArH), 4.07 (s, 3H, CH₂NHCH₃), 2.51 (s, 3H, NHCH₃).

Step 4) Preparation of1-[(1H-Benzimidazol-2-ylmethyl)methylamino]-3-(4-nitrophenoxy-2-propanolDihydrochloride

2-(Methylaminomethyl)benzimidazole (0.459 g, 3.07 mmol) was added to asolution of 2-[(4-nitrophenoxy)methyl]oxirane (0.600 g, 3.07 mmol) inacetonitrile (10 mL). The reaction mixture was stirred at reflux for 18hours, cooled and concentrated in vacuo. The residue was purified bychromatotron (10% methanol/dichloromethane), then treated with ethanolicHCl and ether to afford 0.450 g (34%) of the product as a pale yellowsolid dihydrochloride salt m.p. 207°-209° C.

¹ H NMR (DMSO-d₆): δ8.20 (d, J=9.22 Hz, 2H, ArH), 7.73 (m, 2H, ArH),7.39 (m, 2H, ArH), 7.13 (d, J=9.32 Hz, 2H, ArH), 4.74 (s, 2H, C--CH₂--N--CH₃), 4.45 (br m, 1H, CHOH), 4.15 (m, 2H, OCH₂), 3.43 and 3.37 (m,2H, --CHOHCH₂ --N--), 2.95 (s, 3H, NCH₃).

IR (KBr, cm⁻¹): 3280 (NH.sup.⊕), 1500 (C═N).

MS (m/e): 357 (MH⁺, 94%), 133 (100%).

Anal. Calcd.: C, 50.35; H, 5.16; N, 13.05. Found: C, 50.09; H, 5.02; N,13.04.

EXAMPLE 2N-[4-[3-[(1H-Benzimidazol-2-ylmethyl)methylamino]-2-hydroxypropoxy]phenylmethanesulfonamideStep 1) Preparation of 1-(4-Aminophenoxy)-2,3-propene

To 1-(4-Nitrophenoxy)-2,3-propene, prepared by the process of Example 1,Step 1, (12.65 g, 70.67 mmol) in concentrated HCl (85 mL) at 0° C., wasslowly added stannous chloride (48 g, 212 mmol). After stirring for 20minutes at 55° C., the mixture was cooled to 0° C. and carefullybasified with 50% NaOH. The cloudy mixture was extracted with ether. Theorganic phase was decolorized (charcoal), dried (MgSO₄), andconcentrated to afford product (8.50 g, 81%) as a yellow oil which wasused directly in the next step.

¹ H NMR (CDCl₃): δ7.05 (m, 4H, ArH), 6.4 (m, 1H, OCH₂ --CH═CH₂), 5.70(m, 2H, CH₂ CH═CH₂), 4.80 (d, 2H, OCH₂ CH═CH₂).

Step 2) Preparation of 1-[4-(Methanesulfonamido)phenoxy]-2,3-propene

Methanesulfonyl chloride (5.06 mL, 65.32 mmol) was added to a stirredsolution of 1-(4-aminophenoxy)-2,3-propene (8.11 g, 54.43 mmol) inpyridine (80 mL) at 0° C. The mixture was stirred for 72 hours and wasthen poured slowly into ice-water and extracted with ether. The organicphase was washed with cold 1N HCl and was then extracted with 1N NaOHsolution. The aqueous phase was acidified and the product (9.05 g, 73%)precipitated out as a white solid.

¹ H NMR (CDCl₃): δ7.18 (d, J=6.75 Hz, 2H ArH), 6.88 (d, J=8.94 Hz, 2HArH), 6.00 (m, 1H, CH₂ CH═CH₂), 5.40 and 5.30 (2m, OCH═CH₂), 4.50 (m,OCH₂ CH═CH₂).

Anal. Calcd.: C, 52.85; H, 5.76; N, 6.16. Found: C, 52.80; H, 5.63; N,5.99.

Step 3) Preparation of 2-[(4-(Methanesulfonamido)phenoxy)methyl]oxirane

m-Chloroperoxybenzoic acid (12.16 g, 70.48 mmol) was added to a solutionof 1-[4-(methanesulfonamido)phenoxy]-2,3-propene (8.00 g, 35.24 mmol) indichloromethane (120 mL). The mixture was stirred overnight at reflux,cooled, and filtered. Concentration afforded crude product which waspurified by flash chromatography using 1:1 hexane/ethyl acetate. Yield5.55 g (65%) of white solid.

¹ H NMR (CDCl₃): δ7.17 (d, J=6.87 Hz, 2H ArH), 6.90 (d, J=8.93 Hz, 2H,ArH), 6.40 (br s, NHSO₂ CH₃), 4.20 (dd, J₁ =5.54 Hz, J₂ =2.98 Hz, 1H,epoxide CH₂), 3.90 (dd, H₁ =5.54, J₂ =5.78 Hz, 1H, epoxide CH₂), 3.35(m, 1H, epoxide CH), 2.94 (s, 3H, NHSO₂ CH₃), 2.90 and 2.76 (2m, OCH₂).

IR (KBr): 3240 (NH).

MS (m/z): 243 (60% M⁺), 164 (100%).

Anal. Calcd.: C, 49.37; H, 5.39; N, 5.76. Found: C, 49.69; H, 5.63; N,5.63.

Step 4)N-[4-[3-[(1H-Benzimidazol-2-ylmethyl)methylamino]-2-hydroxypropoxy]phenylmethanesulfonamide

2-(Methylaminomethyl)benzimidazole, prepared by the procedure of Example1, Step 3, (0.993 g, 6.16 mmol) was added to a solution of2-[(4-(methanesulfonamido)phenoxy)methyl]oxirane (1.5 g, 6.16 mmol) inacetonitrile (12 mL). The reaction mixture was stirred at reflux for 18hours, cooled to 0° C. and vacuum filtered. The solids were washed withcold ether and dried under heated vacuum to afford 1.32 g (53%) ofanalytically pure product m.p. 163°-165° C.

¹ H NMR (DMSO-d₆): δ9.33 (br s, 1H, NHSO₂ CH₃), 7.52 and 7.44 (m, 2H,ArH), 7.10 (d, J=9.02 Hz, 2H, ArH), 7.09 (m, 2H, ArH), 6.98 (d, J=8.96Hz, 2H, ArH), 4.93 (br s, 1H, OH), 3.95 (m, 2H, OCH₂), 3.79 (s and m,3H, CH₃ NCH₂ and CHOH), 2.86 (s, 3H, NHSO₂ CH₃), 2.59 and 2.51 (m, 2H,CHOHCH₂ NCH₃), 2.27 (s, 3H, NCH₃).

IR (KBr, cm⁻¹): 3290 (NH).

MS (m/e): 405 (MH⁺, 18%), 131 (100%).

Anal. Calcd.: C, 56.42; H, 5.98; N, 13.85. Found: C, 56.24; H, 5.94; N,13.81.

EXAMPLE 31-[Methyl(2-quinolinylmethyl)amino]-3-(4-nitrophenoxy)-2-propanolDihydrochloride Step 1) Preparation of 2-(Methylaminomethyl)quinoline

2-Chloromethylquinoline hydrochloride (3.00 g, 14.01 mmol) was suspendedin aqueous methylamine (40 mL, 40 wt % in H₂ O) at 10° C. under a N₂atmosphere. After 20 minutes, the reaction mixture was warmed to roomtemperature and stirred for 3 hours. The mixture was diluted with waterand extracted with dichloromethane. The organic extracts were dried(MgSO₄) and concentrated to afford 2.22 g (92%) of pure product as abrown oil.

¹ H NMR (CDCl₃): δ8.08 (m, 2H, ArH), 7.78 (d, J=8.11 Hz, 1H, quinolineH₄), 7.69 (m, 1H, ArH), 7.52 (d, J=7.03 Hz, 1H, ArH), 7.44 (d, J=8.72Hz, 1H, quinoline H₃), 4.06 (s, 2H, CH₂ NHCH₃), 2.55 (s, 3H, NHCH₃).

Step 2) Preparation of1-[Methyl(2-quinolinylmethyl)amino]-3-(4-nitrophenoxy)-2-propanolDihydrochloride

2-(Methylaminomethyl)quinoline (1.76 g, 10.22 mmol) was added to asolution of 2-[(4-nitrophenoxy]methyl]oxirane prepared by the procedureof Example 1, Step 2, (1.00 g, 5.12 mmol) in acetonitrile (10 mL). Thereaction mixture was stirred at reflux for 18 hours, cooled andconcentrated in vacuo. The residue was purified by flash columnchromatography (3% methanol-dichloromethane) and then treated withethanolic HCl and ether to afford 0.510 g (13%) of product as the whitesolid dihydrochloride salt m.p. 154°-157° C.

¹ H NMR (DMSO-d₆): δ10.27 (br s, 1H, NH.sup.⊕), 8.50 (d, J=8.43 Hz, 1H,quinoline H), 8.17 (d, J=9.28 Hz, 2H, ArH), 8.03 (tr, J=6.89 Hz, 2H,ArH), 7.82 (m, 1H, ArH), 7.72 (d, J=8.46 Hz, 1H, quinoline H), 7.67 (m,1H, ArH), 7.07 (d, J=9.26 Hz, 2H, ArH), 4.78 (s, 2H, C--CH₂ NCH₃), 4.50(br m, 1H, CHOH), 4.12 (d, J=5.04 Hz, 2H, OCH₂), 3.50 and 3.36 (m, 2H,CHOH--CH₂ --N), 3.01 (s, 3H, NCH₃).

IR (KBr, cm⁻¹): 3260 (NH⁺).

MS (m/e): 368 (MH⁺).

Anal. Calcd.: C, 54.56; H, 5.27; N, 9.54. Found: C, 55.00; H, 5.58; N,9.16.

EXAMPLE 4N-[4-[2-Hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamide

2-(Methylaminomethyl)quinoline prepared by the procedure of Example 3,Step 1, (1.69 g, 9.86 mmol) in acetonitrile (4 mL) was added to astirring solution of 2-[(4-(methanesulfonamido)phenoxy)methyl]oxiraneprepared by the procedure of Example 2, Step 3, (2.00 g, 8.22 mmol) inacetonitrile (12 mL). The reaction mixture was heated at reflux for 18hours, cooled and concentrated in vacuo. The residue was purified byflash column chromatography (10% methanol-dichloromethane) and thentriturated with ethyl acetate/ether, filtered and dried under heatedvacuum to afford 1.52 g (44%) of analytically pure product m.p.118°-120° C. as a tan solid.

¹ H NMR (DMSO-d₆): δ9.34 (s, 1H, NHSO₂ CH₃), 8.24 (d, J=8.48 Hz, 1H,quinoline H), 7.94 (m, 2H, ArH), 7.72 (m, 1H, ArH), 7.61 (d, J=8.52 Hz,1H, quinoline H), 7.56 (m, 1H, ArH), 7.11 (d, J=9.01 Hz, 2H, ArH), 6.84(d, J=8.93 Hz, 2H, ArH), 5.00 (br d, 1H, OH), 3.96 (m, 2H, OCH₂), 3.82(m, 3H, CCH₂ NCH₃ +CHOH), 2.87 (s, 3H, NHSO₂ CH₃), 2.61 and 2.49(CHOHCH₂ NCH₃), 2.28 (s, 3H, NCH₃).

IR (KBr, cm⁻¹): 3450 (OH), 3180 (NH).

MS (m/e): 416 (MH⁺, 60%).

Anal. Calcd.: C, 60.70; H, 6.06; N, 10.11. Found: C, 60.60; H, 6.08; N,9.85.

EXAMPLE 51-[(2-Benzoxazolylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanolHydrochloride Step 1) Preparation of 2-(Chloromethyl)benzoxazole

A mixture of o-aminophenol (4.00 g, 36.6 mmol) and ethylchloroacetimidate hydrochloride (8.68 g, 54.98 mmol) in ethanol (55 mL)was heated at reflux for 18 hours. The reaction mixture was cooled toroom temperature and vacuum filtered. The filtrate was concentrated invacuo, diluted with dichloromethane and filtered again. The methylenechloride filtrate was dried (MgSO₄) and concentrated to afford 3.99 g(65%) of product as a brown oil which was used directly in the nextstep.

¹ H NMR (CDCl₃): δ7.73 (m, 1H, ArH), 7.56 (m, 1H, ArH), 7.38 (m, 2H,ArH), 4.76 (s, 2H, CH₂ Cl).

Step 2) Preparation of 2-(Methylaminomethyl)benzoxazole

2-(Chloromethyl)benzoxazole (3.99 g, 23.8 mmol) was dissolved in aqueousmethylamine (40 mL, 40 wt % in H₂ O) at 10° C. under a nitrogenatmosphere. After 20 minutes, the reaction mixture was warmed to roomtemperature and stirred for 1 hour. The mixture was diluted with waterand extracted with dichloromethane. The organic phase was dried (MgSO₄)and concentrated to afford crude product which was purified by flashcolumn chromatography (5% methanol/dichloromethane) to afford 3.18 g(82%) of pure product as a yellow oil.

¹ H NMR (CDCl₃): δ7.72 (m, 1H, ArH), 7.54 (m, 1H, ArH), 7.33 (m, 2H,ArH), 4.08 (s, 2H, CH₂ NHCH₃), 2.56 (CH₂ NHCH₃).

Step 3) Preparation of1-[(2-Benzoxazolylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanolHydrochloride

2-(Methylaminomethyl)benzoxazole (1.86 g, 11.53 mmol) was added to asolution of 2-[(4-nitrophenoxy)methyl]oxirane, prepared by the processof Example 1, Step 2, (1.5 g, 7.68 mmol) in acetonitrile (25 mL). Thereaction mixture was heated at reflux for 24 hours and then stirred atroom temperature for an additional 24 hours. The mixture wasconcentrated in vacuo. The residue was purified by chromatotron (10%methanoldichloromethane) then treated with ethanolic HCl and ether toafford 2.12 g (70%) of pure product as the off-white solid hydrochloridesalt m.p. 214°-216° C.

¹ H NMR (DMSO-d₆): δ8.20 (d, J=9.13 Hz, 2H ArH), 7.84 (dd, J₁ =7.67 Hz,J₂ =0.415 Hz, 1H, ArH), 7.80 (dd, J₁ =8.50 Hz, J₂ =1.25 Hz, 1H, ArH),7.50 (m, 1H, ArH), 7.45 (m, 1H, ArH), 7.14 (d, J=9.33 Hz, 2H, ArH), 4.87(s, 2H, C--CH₂ NCH₃), 4.50 (br m, 1H, CHOH), 4.15 (d, J=4.77 Hz, 2H,OCH₂), 3.54 (m, 2H, CHOH--CH₂ N), 3.05 (s, 3H, NCH₃).

IR (KBr, cm⁻¹): 3160 (OH+NH.sup.⊕).

MS (m/e): 358 (MH⁺).

Anal. Calcd.: C, 54.90; H, 5.12; N, 10.67. Found: C, 55.35; H, 5.11; N,10.68.

EXAMPLE 6N-[4-[3-[(2-Benzofuranylmethyl)methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamideStep 1) Preparation of Benzofuran-2-methanol

1 Molar diborane in tetrahydrofuran (61.6 mL, 61.6 mmol) was addeddropwise over 10 minutes to a stirred solution ofbenzofuran-2-carboxylic acid (5.00 g, 30.8 mmol) in tetrahydrofuran (50mL) at 0° C. Stirring was continued at 0° C. for 30 minutes, then atroom temperature for 18 hours. The reaction mixture was quenchedcarefully by slow addition of 1:1 tetrahydrofuran/water, and extractedwith ether. The organic extracts were dried (MgSO₄) and concentrated toafford 3.58 g (78%) of product as a colorless oil.

¹ H NMR (DMSO-d₆): δ7.57 (m, 2H, ArH), 7.27 (m, 2H, ArH), 6.75 (s, 1H,CH═C--), 4.58 (s, 2H, CH₂ OH).

Step 2) Preparation of 2-(Chloromethyl)benzofuran

Thionyl chloride (5.14 mL, 70.46 mmol) was added dropwise to a solutionof benzofuran-2-methanol (3.58 g, 23.48 mmol) and pyridine (10 drops) indichloromethane (60 mL). Stirring was continued at room temperature for18 hours. The mixture was carefully diluted with water and extractedwith methylene chloride. The organic extracts were washed with aqueoussodium bicarbonate, dried (MgSO₄) and concentrated to afford crudeproduct which was purified by flash column chromatography (10% ethylacetate/hexanes) to afford 2.77 g (69%) of pure product as a yellow oil.

¹ H NMR (CDCl₃): δ7.52 (m, 2H, ArH), 7.27 (m, 2H, ArH), 6.73 (s, 1H,CH═C--), 4.69 (s, 2H, CH₂ Cl).

Step 3) Preparation of 2-(Methylaminomethyl)benzofuran

2-(Chloromethyl) benzofuran (2.77 g, 16.63 mmol) was dissolved inaqueous methylamine (40 mL, 40 wt % in H₂ O) at 10° C. under a nitrogenatmosphere. After 10 minutes, the reaction mixture was warmed to roomtemperature and stirring was continued for 72 hours. The mixture wasdiluted with water and extracted with dichloromethane. The organic phasewas dried (MgSO₄) and concentrated to afford crude product which waspurified by flash column chromatography (10% methanol/dichloromethane)to afford 1.00 g (37%) of pure product as a pale yellow oil.

¹ H NMR (CDCl₃): δ7.48 (m, 2H, ArH), 7.21 (m, 2H, ArH), 6.56 (s, 1H,CH═C--), 3.89 (s, 2H, CH₂ NHCH₃), 2.47 (s, 3H, NHCH₃).

Step 4) Preparation ofN-[4-[3-[(2-Benzofuranylmethyl)methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide

2-(Methylaminomethyl)benzofuran (0.927 g, 6.16 mmol) was added to asolution of 2-[(4-(methanesulfonamido)phenoxy)methyl]oxirane (1.4 g,6.16 mmol) in acetonitrile (12 mL). The reaction mixture was heated atreflux for 48 hours, cooled and concentrated in vacuo. The residue waspurified by chromatotron (10% methanol/dichloromethane) twice to affordan oil which was treated with ethanolic HCl and ether to give 0.640 g(25%) of pure product as the white solid hydrochloride salt m.p.182°-183° C.

¹ H NMR (DMSO-d₆): δ9.14 (s, 1H, NHSO₂ CH₃), 7.72 (d, J=7.68 Hz, 1H,ArH), 7.61 (d, J=6.39 Hz, 1H, ArH), 7.39 (m, 1H, ArH), 7.30 (tr, J=7.34Hz, 7.25 Hz, ArH), 7.23 (s, 1H, CH═C--), 7.13 (d, J=8.85 Hz, 2H, ArH),6.88 (d, J=8.93 Hz, 2H, ArH), 6.02 (br m, 1H, OH), 4.65 (br s, 2H,--C--CH₂ NCH₃), 4.41 and 4.29 (br m, 1H, CHOH), 3.91 (d, J=4.98 Hz, 2H,OCH₂), 3.34 (s, 3H, NHSO₂ CH₃), 3.26 (m, 2H, CHOH--CH₂ N), 2.87 (s, 3 H,NCH₃).

IR (KBr, cm⁻¹): 3320 (NH).

MS (m/e): 404 (M⁺), 131 (100%).

Anal. Calcd.: C, 54.48; H, 5.71; N, 6.35. Found: C, 54.43; H, 5.64; N,6.15.

EXAMPLE 71-[(2-Benzofuranylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanolHydrochloride

2-(Methylaminomethyl)benzofuran, prepared by the process of Example 6,Step 3, (0.991 g, 6.14 mmol) was added to a solution of2-[(4-nitrophenoxy)methyl]oxirane, prepared by the process of Example 1,Step 2, (0.600 g, 3.07 mmol) in acetonitrile (10 mL). The reactionmixture was stirred at reflux for 18 hours, cooled and concentrated invacuo. The residue was purified by flash column chromatography (5%methanol/dichloromethane), then treated with ethanolic HCl and ether toafford 0.8 g (66%) of pure hydrochloride salt as a pale yellow solidm.p. 208°-209° C.

¹ H NMR (DMSO-d₆): δ10.44 (br s, 1H, NH.sup.⊕), 8.20 (d, J=9.28 Hz, 2H,ArH), 7.72 (d, J=7.63 Hz, 1H ArH), 7.61 (d, J=8.28 Hz, 1H, ArH), 7.39(m, 1H, ArH), 7.30 (m, 1H, ArH), 7.25 (s, 1H, CH═C--), 7.12 (d, J=9.24Hz, 2H, ArH), 6.12 (br s, 1H, OH), 4.65 (s, 2H, C--CH₂ NCH₃), 4.49 and4.37 (br m, 1H, CHOH), 4.13 (d, J=3.86 Hz, 2H, OCH₂), 3.39 and 3.29 (m,2H, CHOH--CH₂ --N--), 2.87 (s, 3H, NCH₃).

IR (KBr, cm⁻¹): 3220 (NH.sup.⊕).

MS (m/e): 356 (M⁺), 131 (100%).

Anal. Calcd.: C, 58.09; H, 5.39; N, 7.13. Found: C, 58.00; H, 5.61; N,6.92.

EXAMPLE 8N-[4-[3-[Methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamideStep 1) Preparation of 2-[N-[3-(4-Nitrophenoxy)propyl]methylaminomethyl]quinoline

To a stirred suspension of 2-(methylaminomethyl)quinoline, prepared bythe procedure of Example 3, Step 1, (3.67 g, 21.35 mmol), sodium iodide(2.78 g, 18.56 mmol), and potassium carbonate (3.08 g, 138.21 mmol) inacetonitrile (80 mL) was added 1-(4-nitrophenoxy)-3-chloropropane (4.00g, 18.56 mmol). The mixture was stirred at 80° C. overnight,concentrated and partitioned between 10% K₂ CO₃ and ethyl acetate. Theorganic phase was washed with brine, dried (MgSO₄), and concentrated toafford an oil. The product was purified by HPLC (10%methanol/dichloromethane) to afford 2.34 g (36%) of pure product as ayellow oil.

¹ H NMR (CDCl₃): δ8.2-7.9 (m, 4H, quinoline H), 7.7 (m, 2H, quinolineH), 7.5 (d, J=6 Hz, 2H, ArH), 6.8 (d, J=6.2 Hz, 2H, ArH), 4.1 (t, J=4.8Hz, 2H, --OCH₂), 3.8 (s, 2H, --NCH₂), 2.62 (t, J=4 Hz, --CH₂ N--), 2.35(s, 3H, NCH₃), 2.0 (m, 2H, --CH₂ CH₂ CH₂ --).

Step 2) Preparation of 2-[N-[3-(4-Aminophenoxy)propyl]methylaminomethyl]quinoline

A mixture of 2-[N-[3-(4-nitrophenoxy)propyl]methylaminomethyl]quinoline(1.97 g, 5.61 mmol) and 5% Pd/C (0.197 g) in ethyl acetate (40 mL) in aParr reactor was charged with 50 PSI H₂ and left overnight. The mixturewas then filtered through solka floc and concentrated to afford 1.86 g(100%) of amine as a yellow oil which was used directly in the nextstep.

¹ H NMR (CDCl₃): δ8.1 (m, 2H, quinoline H), 7.8-7.4 (m, 4H, quinolineH), 6.70 (br q, 4H, ArH), 3.95 (t, J=4.8 Hz, --OCH₂ --), 3.84 (s, 2H,N--CH₂ --), 3.38 (br s, 2H, --NH₂), 2.64 (t, J=4.8 Hz, --CH₂ --N--),2.31 (s, 3H, --NCH₃), 1.97 (m, 2H, --CH₂ --CH₂ --CH₂ --).

Step 3) Preparation ofN-[4-[3-[Methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamide

Methanesulfonylchloride (0.52 mL, 6.73 mmol) was added dropwise to astirred solution of2-[N-[3-(4-aminophenoxy)propyl]methylaminomethyl]quinoline (1.80 g, 5.61mmol) in pyridine (20 mL) at 0° C. The resulting mixture was stirred atroom temperature overnight. The reaction was quenched with ice chips andextracted with ethyl acetate. The organic phase was dried (MgSO₄),decolorized (charcoal), and concentrated to afford crude product whichwas purified by chromatotron (5% methanol/dichloromethane) to yield 0.88g of an oil which was triturated with ether/hexane to form a white solidm.p. 83°-86° C.

¹ H NMR (CDCl₃): δ8.06 (m, 2H, quinoline H), 7.8 (d, J=8.1 Hz, 1H,quinoline H), 7.7 (m, 1H, quinoline H), 7.58 (d, J=8.47 Hz, 1H,quinoline H), 7.52 (m, 1H, quinoline H), 7.15 (d, J=8.85 Hz, 2H, ArH),6.81 (d, J=8.88 Hz, 2H, ArH), 4.02 (t, J=6.26 Hz, 2H, --OCH₂), 3.86 (s,2H, NCH₂ --), 2.95 (s, 3H --SO₂ CH₃), 2.66 (t, J=6.93 Hz, --CH₂ N--),2.34 (s, 3H, NCH₃), 2.01 (m, 2H, --CH₂ CH₂ CH₂ --)

IR (KBr, cm⁻¹): 2900 (NH).

MS (m/e): 400 (MH⁺, 100%), 259, 144.

Anal. Calcd.: C, 63.13; H, 6.31; N, 10.52. Found: C, 62.86; H, 6.23; N,10.30.

EXAMPLE 9N-[4-[3-[Methyl(2-quinoxalinylmethyl)amino]propoxy]phenyl]methanesulfonamidStep 1) Preparation of 2-(Bromomethyl)quinoxaline

To a stirring solution of 2-methylquinoxaline (20.0 g, 155 mmol) andbenzoyl peroxide (3 g, 12 mmol) in carbon tetrachloride (800 mL) wasadded 1,3-dibromo-5,5-dimethyl hydantoin (22 g, 77 mmol). The resultingmixture was irradiated with a spotlight (200 watt) for 1.5 hours. Themixture was cooled, filtered, and concentrated to afford crude productwhich was purified by HPLC (4:1 hexane/ethyl acetate) to yield 14.0 g(40%) of monobromomethyl product as a grey solid: ¹ H NMR (CDCl₃): δ9.00(s, 1H, ArH), 8.10 (m, 2H, ArH), 7.80 (m, 2H, ArH), 4.72 (s, 2H, BrCH₂--Ar); and 15.0 g (35%) of dibromomethyl product as a white solid: ¹ HNMR (CDCl₃): δ9.39 (s, 1H, ArH), 8.15 (m, 2H, ArH), 7.90 (m, 2H, ArH),6.76 (s, 1H, Br₂ CH--Ar).

Step 2) Preparation of 2-(Methylaminomethyl)quinoxaline

The 2-(bromomethyl)quinoxaline (3.0 g, 13.4 mmol) was added portionwiseto a stirring solution of methylamine (30%) in ethanol (100 mL) at 0° C.The reaction was stirred at 0° C. for 2 hours, concentrated, andpartitioned between 10% aqueous potassium carbonate/ethyl acetate. Theorganic phase was dried (MgSO₄), decolorized (charcoal) andconcentrated. Purification was accomplished by eluting the samplethrough a short silica plug to yield 1.80 g (78%) of a brown oil.

¹ H NMR (CDCl₃): δ8.85 (s, 1H, ArH), 8.10 (m, 2H, ArH), 7.73 (m, 2H,ArH), 4.15 (s, 2H, NCH₂ Ar), 2.60 (s, 3H, NCH₃).

Step 3) Preparation of 1-(4-Nitrophenoxy)-3-iodopropane

To a stirring solution of 4-nitrophenol (10.0 g, 71.94 mmol) intetrahydrofuran (100 mL) at 0° C. was added triphenylphosphine (22.6 g,86.33 mmol), 3-iodopropanol (16.73 g, 89.93 mmol), anddiethylazodicarboxylate (14.3 mL, 86.33 mmol). The resulting mixture wasstirred at 25° C. overnight. The mixture was partitioned between brineand ethyl acetate. The organic phase was dried and concentrated. Theresidue was triturated with 8:1 ether/ethyl acetate to induce theprecipitation of 22 g of triphenylphosphine oxide which was separated byfiltration. The filtrate was preabsorbed onto silica gel andflash-chromatographed (5:1 hexane/ethyl acetate) to afford 17.5 g (79%)of white solid product.

¹ H NMR (CDCl₃): δ8.22 (d, J=8.2 Hz, 2H, ArH), 6.96 (d, J=9.0 Hz, 2H,ArH), 4.15 (t, J=5.8 Hz, 2H, OCH₂), 3.37 (t, J=7.0 Hz, 2H, CH₂ I), 2.31(m, 2H, CH₂ CH₂ CH₂ I).

Step 4) Preparation of 2-[N-[3-(4-Nitrophenoxy)propyl]methylaminomethyl]quinoxaline

To a stirred suspension of 2-(methylaminomethyl)quinoxaline (1.10 g,6.35 mmol) and potassium carbonate (0.88 g, 6.35 mmol) in 2:1acetonitrile/ethanol (40 mL) was added 1-(4-nitrophenoxy)-3-iodopropane(1.95 g, 6.35 mmol). The resulting mixture was heated at 85° C.overnight, concentrated, and partitioned between ethyl acetate and 10%aqueous potassium carbonate. The organic phase was dried (MgSO₄),decolorized (charcoal), and concentrated to afford 1.86 g (83%) ofproduct as a yellow semi-solid which was of sufficient purity to use inthe next step.

¹ H NMR (CDCl₃): δ8.95 (s, 1H, ArH), 8.10 (d, J=9.4 Hz, 2H, ArH), 8.0(m, 2H, ArH), 7.72 (m, 2H, ArH), 6.76 (d, J=9.8 Hz, 2H, ArH), 4.09 (t,J=5.4 Hz, 2H, OCH₂), 2.67 (t, J=5.2 Hz, 2H, CH₂ N), 2.41 (s, 3H, CH₃ N),2.05 (m, 2H, CH₂ CH₂ CH₂).

Step 5) Preparation of 2-[N-[3-(4-Aminophenoxy)propyl]methylaminomethyl]quinoxaline

A mixture of 2-[N-[3-(4-nitrophenoxy)propyl]methylaminomethyl]quinoxaline (1.75 g, 4.97 mmol) and PtO₂ (0.14 g, 0.62 mmol) inethanol (170 mL) was charged with 1 atmosphere H₂ (g). After 30 minutes,the mixture was filtered through solka floc and concentrated to affordcrude product which was purified by HPLC to yield 1.18 g (74%) of ayellow oil.

¹ H NMR (CDCl₃): δ9.00 (s, 1H, ArH), 8.07 (m, 2H, ArH), 7.73 (m, 2H,ArH), 6.70 (d, J=8.2 Hz, 2H, ArH), 6.02 (d, J=9.0 Hz, 2H, ArH), 3.95 (t,J=6 Hz, 2H, OCH₂), 3.89 (s, 2H, NCH₂ Ar), 3.40 (brs, 2H, NH₂), 2.68 (t,J=6.6 Hz, 2H, CH₂ N). 2.33 (s, 3H, NCH₃), 1.99 (m, 2H, CH₂ CH₂ CH₂ N).

Step 6) Preparation ofN-[4-[3-[Methyl(2-quinoxalinylmethyl)amino]propoxy]phenyl]methanesulfonamide

To a stirred solution of2-[N-[3-(4-aminophenoxy)propyl]methylaminomethyl]quinoxaline (0.93 g,2.89 mmol) and pyridine (0.47 mL, 5.78 mmol) in dichloromethane (20 mL)at 0° C. under N₂ was added dropwise methanesulfonyl chloride (0.25 mL,3.21 mmol). The mixture was warmed to 25° C., stirred for 2.5 hours, andthen partitioned between 10% aqueous NaHCO₃ and ethyl acetate. Theorganic phase was washed with brine, dried (MgSO₄), decolorized(charcoal), and concentrated to afford 0.93 g (80%) of product as ayellow oil (one spot by TLC). The compound was treated with ethanolicHCl/ether to afford 0.75 g of the hydrochloride salt as a grey powderm.p. 165°-170° C. (dec.).

¹ H NMR (DMSO-D₆): δ9.42 (s, 1H, NHSO₂ CH₃), 9.20 (s, 1H, ArH), 8.16 (m,2H, ArH), 7.95 (m, 2H, ArH), 7.14 (d, J=9.1 Hz, 2H, ArH), 6.87 (d, J=9.0Hz, 2H, ArH), 4.84 (m, 2H, NCH₂ --Ar), 4.05 (t, J=6 Hz, 2H, OCH₂ --),3.40 (m, 2H, --CH₂ CH₂ CH₂ N), 2.93 (s, 3H, NCH₃), 2.87 (s, 3H, NHSO₂CH₃), 2.26 (m, 2H, CH₂ CH₂ CH₂ --N).

IR (KBr): 2900 (NH).

MS (m/e): 400 (M⁺, 5%), 257, 144.

Anal. Calcd.: C, 54.98; H, 5.77; N, 12.82. Found: C, 54.76; H, 5.87; N,12.60.

EXAMPLE 10N-[2-[[[2-Hydroxy-3-[4-[(methylsulfonyl)amino]phenoxy]propyl]methylamino]methyl]-6-quinolinyl]methanesulfonamideHydrochloride Step 1) Preparation of 2-Methyl-6-nitroquinoline N-oxide

To a stirring solution of 2-methyl-6-nitroquinoline (10.0 g, 53.79 mmol)was added 98% 3-chloroperoxybenzoic acid (11.6 g, 66.10 mmol) indichloromethane (150 mL). The mixture was stirred at 40° C. overnight,filtered and washed with 10% K₂ CO₃ to afford 10.03 (92%) of pureN-oxide.

¹ H NMR (CDCl₃): δ8.94 (d, J=8.90 Hz, 1H, quinoline-H), 8.80 (s, 1H,quinoline-H), 8.49 (d, J=9.22 Hz, 1H, quinoline-H), 7.83 (d, J=9.22 Hz,1H, quinoline-H), 7.52 (d, J=9.10 Hz, 1H, quinoline-H), 2.57 (s, 3H,CH₃).

Step 2) Preparation of 2-(Chloromethyl)-6-nitroquinoline

2-Methyl-6-nitroquinoline N-oxide (13.0 g, 63.72 mmol) was added to astirring solution of p-toluenesulfonyl chloride (13.5 g, 70.81 mmol) indichloroethane (200 mL). The reaction was stirred overnight at 100° C.and then stirred at room temperature for 2 days. To the reaction mixturewas added ethyl acetate. A solid precipitated and was filtered andrecrystallized from acetone/water to afford 7.91 g (56%) of pureproduct.

¹ H NMR (CDCl₃): δ8.80 (d, J=1.8 Hz, quinoline-H), 8.46 (dd, J₁ =10.64Hz, J₂ =1.8 Hz, 1H, quinoline-H), 8.17 (d, J=8.90 Hz, 1H, quinoline-H),7.80 (d, J=9.22 Hz, 1H, quinoline-H), 4.86 (s, 2H, ClCH₂).

Step 3) Preparation of 2-(Methylaminomethyl)-6-nitroquinoline

Methylamine (g) was bubbled through a stirring solution of2-(chloromethyl)-6-nitroquinoline (5.00 g, 22.47 mmol) in toluene (70mL) at 0° C. The mixture was slowly warmed to 20° C. over 4 hours,concentrated to 1/2 volume, and partitioned between 10% aqueous K₂ CO₃/ethyl acetate. The organic phase was dried (MgSO₄), decolorized(charcoal) and concentrated. Yield: 4.89 g as a brown solid which wasused without purification.

¹ H NMR (CDCL₃): δ8.78 (d, J=2.4 Hz, 1H, quinoline H), 8.45 (dd, J₁ =8.2Hz, J₂ =2.4 Hz, 1H, quinoline H), 8.30 (d, J=8.6 Hz, 1H, quinoline H),8.20 (d, J=8.6 Hz, 1H, quinoline H), 7.62 (d, J=8.6 Hz, 1H, quinolineH), 4.14 (s, 2H, NCH₂ --Q), 2.59 (s, 3H, NCH₃).

Step 4) Preparation ofN-[4-[2-Hydroxy-3-[methyl[(6-nitro-2-quinolinyl)methyl]amino]propoxy]phenyl]methanesulfonamide

To a stirring solution of2-[(4-(methanesulfonamido)phenoxy)methyl]oxirane (5.32 g, 21.89 mmol) inethanol (140 mL) was added the 2-(methylaminomethyl)-6-nitroquinoline(4.75, 21.89 mmol) and the resulting mixture was stirred at 50° C.overnight. The reaction mixture was cooled, concentrated, and subjectedto purification by HPLC (10% methanol-ethyl acetate) to afford 1.96 g ofproduct as a yellow amorphous solid.

¹ H NMR (CDCL₃): δ8.75 (d, J=2 Hz, 1H, quinoline H), 8.45 (dd, J₁ =9.6Hz, J₂ =2 Hz, 1H, quinoline H), 8.30 (d, J=9.0 Hz, 1H, quinoline H),8.18 (d, J=9.0 Hz, 1H, quinoline H), 7.64 (d, J=7.8 Hz, 1H, quinolineH), 7.15 (d, J=7.3 Hz, 2H, aromatic H), 6.80 (d, J=7.3 Hz, 2H, aromaticH), 4.25-3.80 (m, 5H, OCH₂ and CHOH and NCH₂ --Q), 2.92 (s, 3H, NHSO₂CH₃), 2.75 (brd, 2H, CHOHCH₂ N), 2.45 (s, 3H, NCH₃).

Step 5) Preparation ofN-[4-[3-[[(6-Amino-2-quinolinyl)methyl]methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide

N-[4-[2-Hydroxy-3-[methyl[(6-nitro-2-quinolinyl)methyl]amino]propoxy]phenyl]methanesulfonamide(1.20 g, 2.61 mmol) and PtO₂ (0.120 g, 10% by wt.) were suspended inethanol (100 mL) and the flask was charged with H₂ (1 atm). Afterstirring for 6 hours, the mixture was filtered through a pad of solkafloc and the filtrate was concentrated in vacuo to afford 1.00 g ofproduct as a pale oil which was used directly in the next step.

¹ H NMR (DMSO-d₆): δ9.45 (brs, 1H, NHSO₂ CH₃), 7.93 (d, J=7.8 Hz, 1H,quinoline H), 7.70 (d, J=9 Hz, 1H, quinoline H), 7.41 (d, J=9 Hz, 1H,quinoline H), 7.2 (m, 3H, quinoline H and aromatic H), 6.95 (m, 2H,aromatic H), 6.80 (s, 1H, quinoline H), 5.60 (brs, 2H, NH₂), 5.10 (m,1H, --OH), 4.15-3.65 (m, 5H, OCH₂ and CHOH and NCH₂ --Q), 2.93 (s, 3H,NHSO₂ CH₃), 2.60 (m, 2H, CHCH₂ N), 2.35 (s, 3H, NCH₃).

Step 6) Preparation of N-[2-[[[2-Hydroxy-3-[4-[(methylsulfonyl)amino]phenoxy]propyl]methylamino]methyl]-6-quinolinyl]methanesulfonamideHydrochloride

ToN-[4-[3-[[(6-amino-2-quinolinyl)methyl]methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide(0.94 g, 2.19 mmol) in water (10 mL) at 0° C. was added methanesulfonicacid (0.14 mL, 2.19 mmol) and methanesulfonyl chloride (0.30 mL, 3.93mmol). After stirring for 18 hours at 25° C. the pH was adjusted to 6with K₂ CO₃ and an additional 0.30 mL of methanesulfonyl chloride wasadded. The mixture stirred for an additional 20 hours, and was thenreadjusted to pH=6 and re-charged with 0.30 mL methanesulfonyl chloride.Upon completion (TLC), the reaction mixture was diluted with 10% aqueousNaHCO₃ and extracted with 4:1 dichloromethane/isopropanol. The organicphase was dried (MgSO₄), decolorized (charcoal) and concentrated toafford product that was purified by HPLC (5% methanol/ethyl acetate;w/ammonium hydroxide). Yield: 0.34 g (31%) as an amorphous solid. Thiswas converted to its hydrochloride by treatment with 1N HCl/ether andethanol. Yield: 0.25 g as a light yellow solid.

¹ H NMR (DMSO-d₆): δ10.31 (s, 1H, NHSO₂ CH₃), 10.04 (brs, 1H, HCl), 9.40(s, 1H, NHSO₂ CH₃), 8.43 (d, J=8.34 Hz, 1H, quinoline H), 8.00 (d,J=9.05 Hz, 1H, quinoline H), 7.77 (d, J=2.42 Hz, 1H, quinoline H), 7.65(dd, J₁ =8.65 Hz, J₂ =2.34 Hz, 2H, quinoline H), 7.11 (d, J=9.02 Hz, 2H,aromatic H), 6.85 (d, J=9.02 Hz, 2H, aromatic H), 5.97 (brs, 1H, OH),4.73 (m, 2H, OCH₂ CHOH), 4.41 (m, 1H, CHOH), 3.91 (m, 2H, NCH₂ Q), 3.38(m, 2H, CH₂ N), 3.11 (s, 3H, NHSO₂ CH₃), 2.97 (s, 3H, NCH₃), 2.87 (s,3H, NHSO₂ CH₃).

IR (KBr) cm⁻¹ 3250 (OH).

MS (m/e): 509 (MH⁺, 10%), 275, 188.

Anal. Calcd.: C, 46.77; H, 5.41; N, 9.92. Found: C, 46.59; H, 5.55; N,9.53.

EXAMPLE 11N-[4-[3-[[(6-Fluoro-2-quinolinyl)methyl]methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamideHydrochloride Step 1) Preparation of 6-Fluoro-2-methylquinoline N-Oxide

To a stirring suspension of 6-fluoro-2-methylquinoline (7.0 g, 43.42mmol) in dichloroethane (150 mL) was added 98% 3-chloroperoxybenzoicacid (7.5 g, 42.73 mmol). The mixture was stirred overnight at 40° C.,concentrated and partitioned between 10% K₂ CO₃ and ethyl acetate. Theorganic phase was dried over MgSO₄ and concentrated to afford a solid.The product was purified by HPLC (5% methanol/dichloromethane) to afford3.14 g (41%) of pure N-oxide.

¹ H NMR (CDCl₃): δ8.80 (m, 2H, quinoline H), 7.80-7.25 (m, 4H,quinoline-H), 2.65 (s, 3H, CH₃).

Step 2) Preparation of 2-(Chloromethyl)-6-fluoroquinoline

6-Fluoro-2-methylquinoline N-oxide (2.70 g, 15.25 mmol) was added to astirring solution of p-toluenesulfonyl chloride (2.9 g, 15.21 mmol) indichloroethane (100 mL). The reaction mixture was heated to 100° C.overnight under N₂, cooled and concentrated, partitioned between 10% K₂CO₃ /ethyl acetate, dried over MgSO₄ and evaporated under reducedpressure to afford a solid. The crude solid was purified by flashchromatography (15:1 hexane/ethyl acetate) to afford 1.59 g (63%) ofpure product as an off white solid.

¹ H NMR (CDCl₃): δ8.25-7.28 (m, 5H, quinoline H), 4.84 (s, 2H, ClCH₂).

Step 3) Preparation ofN-[4-[3-[[(6-Fluoro-2-quinolinyl)methyl]methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamideHydrochloride

2-(Chloromethyl)-6-fluoroquinoline (1.89 g, 9.69 mmol) was dissolved inethanolic methylamine (30 mL, 33% by wt) at 0° C. under N₂. After 10minutes the reaction was warmed to room temperature and stirring wascontinued for 2 hours. The mixture was concentrated, partitioned between10% K₂ CO₃ /ethyl acetate, dried over MgSO₄ and evaporated under reducedpressure to afford an oil. The crude oil was purified by flash columnchromatography (5% methanol/dichloromethane) to afford 0.83 g (49%) ofpure product as a pale yellow oil which was treated immediately with2-[(4-(methanesulfonamido)phenoxy)methyl]oxirane (1.0 g, 4.09 mmol) inethanol (20 mL). The reaction was stirred at room temperature for 24hours and concentrated in vacuo. The organic mixture was partitionedbetween 10% K₂ CO₃ /ethyl acetate, dried over MgSO₄, and evaporatedunder reduced pressure to afford a crude product which was purified byflash chromatography (5% methanol/dichloromethane to afford 0.70 g ofproduct (40%). The oil was converted to the HCl salt by adding 1.0equivalent of 1N HCl in diethyl ether and isolating 0.54 g (30%) as thehydrate.

¹ H NMR (DMSO-d₆): δ10.00 (s, 1H, HCl), 9.41 (s, 1H, NHSO₂ CH₃), 8.49(d, J=8.72 Hz, 1H, quinoline-H), 8.09 (m, 1H, quinoline H), 7.87 (m, 1H,quinoline-H), 7.76 (m, 2H, quinoline-H), 7.13 (d, J=8.92 Hz, 2H, Ar--H),6.86 (d, J=9.13 Hz, 2H, Ar--H), 6.00 (brs, 1H, OH), 4.77 (m, 2H, OCH₂CHOH), 4.41 (m, 1H, CHOH), 3.92 (m, 2H, N--CH₂ --quinoline), 3.40 (m,2H, CHOHCH₂ NCH₃), 2.99 (s, 3H, NHSO₂ CH₃), 2.87 (s, 3H, NCH₃).

IR (KBr): cm⁻¹ 3400 (OH), 3125 (NH).

MS (m/e): 434 (MH⁺, 30%).

Anal. Calcd.: C, 52.26; H, 5.51; N, 8.70. Found: C, 52.37; H, 5.53; N,8.42.

EXAMPLE 12N-[4-[3-[[(6-Chloro-2-quinolinyl)methyl]methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamideHydrochloride Step 1) Preparation of 6-Chloro-2-methylquinoline N-Oxide

To stirring suspension of 6-chloro-2-methylquinoline (5.0 g, 28.14 mmol)in dichloromethane (150 mL) was added 98% 3-chloroperoxybenzoic acid(4.8 g, 28.00 mmol). The mixture was stirred overnight at 40° C. It wasconcentrated and partitioned between 10% K₂ CO₃ /ethyl acetate. Theorganic phase was dried over MgSO₄ and concentrated to afford a crudesolid. The product was purified by flash chromatography (5%methanol/dichloromethane) to afford 1.85 g (34%) of pure N-oxide.

¹ H NMR (CDCl₃): δ8.70 (d, J=9.20 Hz, 1H, quinoline-H), 7.81 (d, J=1.80Hz, 1H, quinoline-H), 7.67 (dd, J=8.90 Hz, J₂ =1.8 Hz, 1H, quinoline-H),7.55 (d, J=8.90 Hz, 1H, quinoline-H), 7.37 (d, J=8.80 Hz, 1H,quinoline-H), 2.70 (s, 3H, CH₃).

Step 2) Preparation of 6-Chloro-2-chloromethylquinoline

6-Chloro-2-methylquinoline N-oxide (1.73 g, 8.1 mmol) was added to astirring solution of p-toluenesulfonyl chloride (1.7 g, 8.96 mmol) indichloroethane (80 mL). The reaction mixture was heated to 100° C.overnight under N₂, cooled and concentrated, partitioned between 10% K₂CO₃ /ethyl acetate, dried over MgSO₄, and evaporated under reducedpressure to afford a solid. The crude solid was purifed by flashchromatography (4:1 hexane/ethyl acetate) to afford 0.93 g (52%) of pureproduct as an off white solid.

¹ H NMR (CDCl₃): δ8.20-7.60 (m, 5H, quinoline-H), 4.80 (s, 2H, ClCH₂).

Step 3) Preparation ofN-[4-[3-[[(6-Chloro-2-quinolinyl)methyl]methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamideHydrochloride

6-Chloro-2-chloromethylquinoline (1.34 g, 6.32 mmol) was dissolved inethanolic methylamine (30 mL, 33% by wt.) at 0° C. under N₂. After 10minutes the reaction was warmed to room temperature and stirring wascontinued for 2 hours. The mixture was concentrated, partitioned between10% K₂ CO₃ /ethyl acetate, dried over MgSO₄ and evaporated under reducedpressure to afford an oil. The product was purified by flashchromatography (5% methanol/dichloromethane) to afford 0.37 g (28%) ofmethylamino compound as a pale yellow oil which was treated immediatelywith 2-[(4-(methanesulfonamido)phenoxy)methyl]oxirane (0.43 g, 1.76mmol) in ethanol (15 mL).

The reaction mixture was stirred at 20° C. for 24 hours and concentratedin vacuo. The organic mixture was partitioned between 10% K₂ CO₃ /ethylacetate, dried over MgSO₄, and evaporated under reduced pressure toafford a crude oil. The oil was purified by flash column chromatography(5% methanol/dichloromethane) to afford 0.33 g of pure product (33%).The oil was then converted to HCl salt by adding 1.0 equivalent of 1NHCl in diethyl ether and isolating 0.12 g of the solid as a hydrate.

¹ H NMR (DMSO-d₆): δ10.09 (s, 1H, HCl), 9.39 (s, 1H, NHSO₂ CH₃), 8.47(d, J=8.00 Hz, 1H, quinoline-H), 8.20 (d, J=1.62 Hz, 1H, quinoline-H),8.03 (d, J=8.92 Hz, 1H, quinoline-H), 7.84 (dd, J=9.02 Hz, J₂ =2.40 Hz,1H, quinoline-H), 7.73 (d, J=8.52 Hz, 1H, quinoline-H), 7.12 (d, J=9.00,Hz, 2H, Ar--H), 6.85 (d, J=8.95 Hz, 2H, Ar--H), 6.00 (bs, 1H, OH), 4.76(m, 2H, OCH₂ CHOH), 4.41 (m, 1H, CHOH), 3.92 (m, 2H, CH₂ --Q), 3.39 (m,2H, CHOHCH₂ NCH₃), 2.99 (s, 3H, NCH₃ ), 2.86 (s, 3H, HNSO₂ CH₃).

IR (KBr) cm⁻¹ 3375 (OH), 3075 (NH).

MS (m/e) 450 (MH⁺, 100%).

Anal. Calcd.: C, 51.09; H, 5.26; N, 8.51. Found: C, 51.30; H, 5.57; N,8.24.

EXAMPLE 13N-[4-[2-Hydroxy-3-[[(6-methoxy-2-quinolinyl)methyl]methylamino]propoxy]phenyl]methanesulfonamideHydrochloride Step 1) Preparation of 6-Methoxyquinaldine N-Oxide

6-Methoxyquinaldine (7.0 g, 40.40 mmol) was added to a stirring solutionof 98% 3-chloroperoxybenzoic acid (11.5 g, 65.30 mmol) in dichloroethane(150 mL). The reaction was heated to 40° C. overnight, partitionedbetween 10% K₂ CO₃ /ethyl acetate, dried over MgSO₄ and evaporated underreduced pressure to afford a crude solid which was purified by flashcolumn chromatography (5% methanol/dichloromethane) to afford 6.54 g ofpure N-oxide.

¹ H NMR (CDCl₃): δ8.70 (d, J=9.20 Hz, 1H, quinoline-H), 7.93 (d, J=8.83Hz, 1H, quinoline-H), 7.76 (d, J=9.22 Hz, 1H, quinoline-H), 7.70 (m, 2H,quinoline-H), 3.89 (s, 3H, OCH₃), 2.80 (s, 3H, CH₃).

Step 2) Preparation of 2-(Chloromethyl)-6-methoxyquinoline

6-Methoxyquinaldine N-Oxide (6.94 g, 36.71 mmol) was added to a stirringsolution of p-toluenesulfonylchloride (7.0 g, 36.84 mmol) indichloroethane (100 mL). The reaction was heated to 100° C. overnight,partitioned between 10% K₂ CO₃ /ethyl acetate, dried over MgSO₄, andevaporated under reduced pressure. The crude solid was purified by HPLCto afford 2.6 g (37%) of chloride.

¹ H NMR (CDCl₃): δ8.09 (d, J=9.22 Hz, 1H, quinoline-H), 7.99 (d, J=9.2Hz, 1H, quinoline-H), 7.52 (d, J=9.22 Hz, 1H, quinoline-H), 7.40 (dd, J₁=9.22 Hz, J₂ =3.0 Hz, 1H, quinoline-H), 7.13 (d, J=3.0 Hz, 1H,quinoline-H), 4.80 (s, 3H, ClCH₂), 3.92 (s, 3H, OCH₃).

Step 3) Preparation of 6-Methoxy-2-(methylamino)methylquinoline

2-(Chloromethyl)-6-methoxyquinoline (0.40 g, 2.05 mmol) was dissolved inethanolic methylamine (15 mL, 33 wt % in EtOH) at 0° C. under a nitrogenatmosphere. After 10 minutes the reaction mixture was warmed to roomtemperature and stirring was continued for 1.5 hours. The reactionmixture was concentrated, partitioned between 10% K₂ CO₃ /ethyl acetate,dried over MgSO₄ and evaporated under reduced pressure to afford 0.30 g(76%) of a pale yellow oil which was used directly in the next step.

¹ H NMR (CDCl₃): δ8.0 (m, 2H, quinoline-H), 7.40 (m, 2H, quinoline-H),7.07 (d, J=3.0 Hz, quinoline-H), 4.0 (s, 2H, NCH₂ Q) 3.90 (s, 3H, OCH₃),2.52 (s, 3H, NCH₃).

Step 4) Preparation ofN-[4-[2-Hydroxy-3-[[(6-methoxy-2-quinolinyl)methyl]methylamino]propoxy]phenyl]methanesulfonamideHydrochloride

6-Methoxy-(2-methylaminomethylquinoline (0.30 g, 1.48 mmol) was added toa stirring solution of 2-[(4-(methanesulfonamido)phenoxy)methyl]oxirane(0.35 g, 1.43 mmol) in ethanol (15 mL). The reaction mixture stirred atroom temperature overnight under N₂, and was concentrated in vacuo. Theresidue was purified by flash column chromatography (5%methanol/dichloromethane) to afford 0.80 g of a pale yellow oil. Thefree base was converted to its HCl salt by adding 1.0 equivalent of 1NHCl in diethyl ether to afford 0.30 g (47%) of the solid as a hydrate.

¹ H NMR (DMSO-d₆): δ9.40 (s, 1H, HNSO₂ CH₃), 8.39 (d, J=9.22 Hz, 1H,quinoline-H), 7.92 (d, J=8.90 Hz, 1H, quinoline-H), 7.65 (d, J=9.42 Hz,1H, quinoline-H), 7.43 (m, 2H, quinoline-H), 7.12 (d, J=9.01 Hz, 2H,Ar--H), 6.84 (d, J=8.84 Hz, 1H, Ar--H), 5.95 (s, 1H, OH), 4.67 (m, 2H,OCH₂), 4.41 (m, 1H, CHOH), 3.91 (m and s, 5H, CH₂ -quinoline and OCH₃).3.40 (m, 2H, CHOHCH₂ N), 2.95 (bs, 3H, NCH₃), 2.86 (s, 3H, NHSO₂ CH₃).

IR (KBr): cm⁻¹ 3400 (OH), 3100 (NH).

MS (m/e): 446 (MH⁺, 20%).

Anal. Calcd.: C, 52.82; H, 5.84; N, 8.40. Found: C, 52.45; H, 6.06; N,8.04.

EXAMPLE 14N-[2-[[Methyl[3-[4-[(methylsulfonyl)amino]phenoxy]propyl]amino]methyl]-6-quinolinyl]methanesulfonamideStep 1) Preparation of N-[3-(4-Nitrophenoxy)propyl]methylamineHydrochloride

1-(4-Nitrophenoxy)-3-iodopropane (4.76 g, 15.50 mmol) was addedportionwise to a stirring solution of methylamine (33%) in ethanol (100mL) at 0° C. The mixture stirred at room temperature for 4 hours and wasthen concentrated. The residue was partitioned between ethyl acetate/10%aqueous K₂ CO₃. The organic phase was dried, decolorized andconcentrated to afford an oil which was treated with ethanolic HCl.Yield: 2.5 g of hydrochloride salt which was used without purification.

¹ H NMR (DMSO-d₆): δ9.15 (br s, 2H, N.sup.⊕ H₂), 8.20 (d, J=9.0 Hz, 2H,aromatic H), 7.15 (d, J=9 Hz, 2H, aromatic H), 4.20 (t, J=7.2 Hz, 2H,OCH₂), 3.00 (m, 2H, CH₂ N), 2.51 (s, 3H, NCH₃), 2.15 (m, 2H, OCH₂ CH₂CH₂ N).

Step 2) Preparation ofN-Methyl-6-nitro-N-[(4-nitrophenoxy)propyl]-2-quinoline-methanamine

N-[3-(4-Nitrophenoxy)propyl]methylamine hydrochloride (3.08 g, 12.49mmol), 2-(chloromethyl)-6-nitroquinoline (2.78 g, 12.49 mmol), andpotassium carbonate (3.45 g, 25.0 mmol) were stirred in 2:1acetonitrile/ethanol (120 mL) at reflux for 18 hours. The mixture wasconcentrated and the residue was partitioned between 10% aqueous K₂ CO₃and 4:1 dichloromethane/isopropanol. The organic phase was dried,decolorized and concentrated to afford crude product which was purifiedby column chromatography (1:2 hexane/ethyl acetate). Yield: 2.63 g (53%)as a yellow oil.

¹ H NMR (CDCl₃): δ8.70 (d, J=2.4 Hz, 1H, quinoline H), 8.43 (dd, J₁ =9.8Hz, J₂ =2.4 Hz, 1H, quinoline H), 8.15 (m, 3H, quinoline H, and 2aromatic H), 2.70 (d, J=9.0 Hz, 1H, quinoline H), 6.92 (m, 3H, quinolineH, and aromatic H), 4.12 (t, J=6.6 Hz, 2H, OCH₂), 3.85 (s, 2H, NCH₂ -Q),2.64 (t, J=6.6 Hz, 2H, CH₂ N), 2.36 (s, 3H, NCH₃), 2.02 (m, 2H, OCH₂ CH₂CH₂ N).

Step 3) Preparation of6-Amino-N-[(4-aminophenoxy)propyl]-N-methyl-2-quinoline methanamine

N-Methyl-6-nitro-N-[(4-nitrophenoxy)propyl]-2-quinoline methanamine(2.60 g, 6.57 mmol) was dissolved in ethanol (170 mL) containing PtO₂(0.39 g). The mixture was charged with H₂ (g) (1 atm), stirred for 4hours, and filtered through a pad of solka floc. The filtrate wasconcentrated to afford 2.18 g of product as a yellow oil that was useddirectly without purification.

¹ H NMR (CDCl₃): δ7.83 (m, 2H, quinoline H), 7.45 (d, J=7.8 Hz, 1H,quinoline H), 7.12 (dd, J₁ =7.6 Hz, J₂ =2.4 Hz, 1H, quinoline H), 6.87(d, J=2.4 Hz, 1H, quinoline H), 6.70 (m, 4H, aromatic H), 3.95 (t, J=6.6Hz, 2H, OCH₂), 3.75 (s, 2H, NCH₂ --Q), 2.60 (t, J=7.0 Hz, 2H, CH₂ N),2.30 (s, 3H, NCH₃), 1.95 (m, 2H, OCH₂ CH₂ CH₂ N).

Step 4) Preparation ofN-[2-[[Methyl[3-[4-[(methylsulfonyl)amino]phenoxy]propyl]amino]methyl]-6-quinolinyl]methanesulfonamide

Methanesulfonyl chloride (1.10 mL, 14.27 mmol) was added dropwise to astirring solution of6-amino-N-[(4-aminophenoxy)propyl]-N-methyl-2-quinoline methanamine(2.18 g, 6.49 mmol) in pyridine (30 mL) at 0° C. under N₂ (g). Theresulting mixture was stirred at room temperature for 3 hours, dilutedwith ice water containing NaHCO₃, and extracted with 4:1dichloromethane/isopropanol. The organic phase was dried (MgSO₄),decolorized (charcoal), and concentrated to afford product which waspurified by HPLC (10% methanol/dichloromethane). Yield: 1.30 g of awhite solid.

¹ H NMR (DMSO-d₆): δ10.20 and 9.32 (2 brs, 2H, NHSO₂ CH₃), 8.17 (d,J=8.51 Hz, 1H, quinoline H), 7.92 (d, J=8.92 Hz, 1H, quinoline H), 7.67(d, J=2.49 Hz, 1H, quinoline H), 7.55 (m, 2H, quinoline H), 7.12 (d,J=8.92 Hz, 2H, aromatic H), 6.85 (d, J=9.13 Hz, 2H, aromatic H), 3.99(t, J=6.43 Hz, 2H, OCH₂), 3.74 (s, 2H, NCH₂ --Q), 3.07 and 2.87 (2s, 6H,--NHSO₂ CH₃), 2.55 (m, 2H, CH₂ N), 2.21 (s, 3H, NCH₃), 1.91 (m, 2H, OCH₂CH₂ CH₂ N).

IR (KBr): cm⁻¹ 2940 (NH).

MS (m/e) 493 (MH⁺, 10%), 259, 237, 188.

Anal. Calcd. (with 0.1 mole water): C, 53.45; H, 5.75; N, 11.33. Found:C, 52.77; H, 5.36; N, 11.12.

EXAMPLE 15N-[4-[2-Hydroxy-3-[methyl(2-quinoxalinylmethyl)amino]propoxy]phenyl]methanesulfonamideEthanedioate (1:1 salt)

2-(Methylaminomethyl)quinoxoline (2.40 g, 13.86 mmol) was added to astirring solution of the2-[(4-(methanesulfonamido)phenoxy)methyl]oxirane (3.38 g, 13.86 mmol) inethanol (150 mL). The reaction was stirred at room temperature for 24hours and concentrated in vacuo. The organic mixture was partitionedbetween 10% K₂ CO₃ /ethyl acetate, dried over MgSO₄ and evaporated underreduced pressure to afford a crude oil. The oil was purified by flashchromatography (5% methanol/dichloromethane) to afford 2.78 g of oil(49%) which was then converted to the oxalate salt by adding 1.0equivalent of oxalic acid and isolating 0.87 g of the solid.

¹ H NMR (DMSO-d₆): δ9.35 (s, 1H, NHSO₂ CH₃), 9.02 (s, 1H,quinoxoline-H), 8.07 (m, 2H, quinoxaline-H), 7.85 (m, 2H,quinolxoline-H), 7.09 (d, J=8.98 Hz, 2H, Ar--H), 6.82 (d, J=9.01 Hz, 2H,Ar--H), 4.21 (m, 2H, OCH₂ CHOH), 4.10 (m, 1H, CHOH), 3.87 (m, 2H, NCH₃-quinoxaline), 2.94 (m, 5H, CHOHCH₂ NHSO₂ CH₃), 2.52 (s, 3H, NCH₃).

IR (KBr): cm⁻¹ 3400 (OH), 3200 (NH).

MS (m/e). 417 (MH⁺, 40%).

Anal. Calcd.: C, 52.17; H, 5.41; N, 11.06. Found: C, 52.10; H, 4.91; N,10.92.

EXAMPLE 16(+)-(R)-N-[4-[2-Hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamideStep 1) Preparation of (R)-(-)-2-[(4-Nitrophenoxy)methyl]oxirane

To a solution of sodium 4-nitrophenoxide (2.38 g, 11.57 mmol) indimethylformamide (15 mL) at 0° C. was added2-(R)-(-)-glycidyl-3-nitrobenzenesulfonate (3.00 g, 11.57 mmol). Themixture was stirred for 18 hours under N₂ at 20° C. The reaction mixturewas worked up and purified as in the case of the enantiomer to afford1.83 g (81%) of product as a white solid.

¹ H NMR (CDCl₃): δ8.20 (d, J=9 Hz, 2H, ArH), 7.00 (d, J=9 Hz, 2H, ArH),4.39 and 4.00 (2m --OCH₂ --CH), 3.38 (m, 1H, epoxide methine), 2.90 and2.79 (2m, 2H, epoxide methylene); [α]_(D) ²⁵ =-11.0° (CH₃ OH).

Step 2) Preparation of(R)-1-[Methyl(2-quinolinylmethyl)amino]-3-(4-nitrophenoxy)-2-propanol

2-(Methylaminomethyl)quinoline (5.57 g, 32.41 mmol) in acetonitrile (30mL) was added to a stirring solution of(R)-(-)-2-[(4-nitrophenoxy)methyl]oxirane (6.32 g, 32.41 mmol) inacetonitrile (90 mL) and the mixture was stirred 18 hours at 60° C.,then 48 hours at 20° C. The solvent was removed in vacuo, and theresidue was partitioned between ethyl acetate/brine. The organic layerwas dried, decolorized, and concentrated to afford crude product whichwas used directly in the next step.

¹ H NMR (CDCl₃): δ8.15 (m, 4H, 2 quinoline H and 2 aromatic H), 7.80 (d,J=7.8 Hz, 1H, quinoline H), 7.72 (m, 1H, quinoline H), 7.52 (m, 1H,quinoline H), 7.41 (d, J=8.4 Hz, 1H, quinoline H), 6.90 (d, J=9.6 Hz,2H, aromatic H), 5.13 (brs, 1H, OH), 4.23-3.90 (m, 5H, OCH₂ CHOH andJ=9.6 Hz, 2H, aromatic H), 5.13 (brs, 1H, OH), 4.23-3.90 (m, 5H, OCH₂CHOH and NCH₂ Q), 2.78 (m, 2H, CH₂ N), 2.49 (s, 3H, NCH₃).

Step 3) Preparation of(+)-(R)-N-[4-[2-Hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamide

(R)-1-[Methyl(2-quinolinylmethyl)amino]-3-(4-nitrophenoxy)-2-propanol(10.00 g, 27.25 mmol) was dissolved in ethanol (200 mL) containing 5%Pd/C (1.0 g). The Parr vessel was charged with H₂ (50 psi). After 18hours, the mixture was filtered through celite, and then concentrated toafford crude product which was purified by HPLC (methanol/ethyl acetate)to give 5.96 g (65%) of product as a yellow oil. This was dissolved inwater (50 mL) at 0° C. and to it was added methanesulfonic acid (1.15mL, 17.69 mmol) followed by methanesulfonyl chloride (2.05 mL, 26.53mmol) dropwise and the mixture was then stirred for 3 hours at roomtemperature. The pH was adjusted to 6 using K₂ CO₃ and an additional 2mL of methanesulfonyl chloride was added. The mixture was stirredovernight and was then recharged with additional methanesulfonylchloride (2 mL) and allowed to stir for an additional 2 days. Thereaction mixture was partitioned between 10% NaHCO₃ and 4:1dichloromethane/isopropanol. The organic phase was dried, decolorizedand concentrated to afford a brown solid which was recrystallized fromethyl acetate/hexanes to afford 5.40 g (74%) of analytically purematerial. [a]_(D) ²⁵ =+16.5 (CH₃ OH).

¹ H NMR (CDCl₃): δ8.13 (d, J=8.51 Hz, 1H, quinoline H), 8.09 (d, J=8.51Hz, 1H, quinoline H), 7.81 (d, J=8.09 Hz, 1H, quinoline H), 7.70 (m, 1H,quinoline H), 7.53 (m, 1H, quinoline H), 7.46 (d, J=8.51 Hz, 1H,quinoline H), 7.15 (d, J=8.92 Hz, 2H, aromatic H), 6.84 (d, J=9.13 Hz,2H, aromatic H), 4.20 (m, 1H, CHOH), 4.10-3.90 (m, 4H, OCH₂ and NCH₂ Q),2.92 (s, 3H, NHSO₂ CH₃), 2.77 (m, 2H, CHOHCH₂ N), 2.51 (s, 3H, NCH₃).

IR (KBr) cm⁻¹ 3400 (OH), 3180 (NH).

MS (m/e) 416 (MH⁺).

Anal. Calcd.: C, 60.70; H, 6.06; N, 10.11. Found: C, 60.83; H, 6.17; N,9.81.

EXAMPLE 17(-)-(S)-N-[4-[2-Hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamideStep 1) Preparation of (S)-(+)-2-[(4-Nitrophenoxy)methyl]oxirane

To a solution of sodium 4-nitrophenoxide (3.18 g, 15.43 mmol) indimethylformamide (20 mL) at 0° C. was added2-(S)-(+)-glycidyl-3-nitrobenzenesulfonate (4.00 g, 15.43 mmol). Themixture was stirred for 18 hours under N₂ at 20° C. The reaction mixturewas diluted with brine (50 mL) and extracted with ethyl acetate. Thecombined organic phase was washed with cold 0.1N NaOH, water, and brine.The extract was dried (MgSO₄) and concentrated to afford 3.0 g ofproduct which was purified by flash column chromatography using 2:1hexane/ethyl acetate to afford 2.49 g (83%) of product as a white solid.

¹ H NMR (CDCl₃): δ8.20 (d, J=9 Hz, 2H, ArH), 7.00 (d, J=9 Hz, 2H, ArH),4.39 and 4.00 (2m, --OCH₂ --CH), 3.38 (m, 1H, epoxide methine), 2.90 and2.80 (2m, 2H, epoxide methylene); [α]_(D) ²⁵ =+10.6° (CH₃ OH).

Step 2) Preparation of(S)-1-[Methyl(2-quinolinylmethyl)amino]-3-(4-nitrophenoxy)-2-propanol

2-(Methylaminomethyl)quinoline (4.47 g, 25.96 mmol) in acetonitrile (30mL) was added to a stirring solution of(S)-(+)-2-[(4-nitrophenoxy)methyl]oxirane (4.23 g, 21.67 mmol) inacetonitrile (10 mL). The reaction was lightly refluxed under N₂ for 24hours, cooled and concentrated in vacuo. The residue was purified byHPLC dried and heated under vacuum to afford 5.01 g (63%) of productwhich was used directly in the next step.

¹ H NMR (CDCl₃): δ8.15 (m, 4H, quinoline-H and Ar--H), 7.75 (d, J=8.0Hz, 1H, quinoline-H), 7.70 (m, 1H, quinoline-H), 7.50 (m, 1H,quinoline-H), 7.40 (d, J=8.0 Hz, 1H, quinoline-H), 6.90 (d, J=9.6 Hz,2H, Ar--H), 5.12 (bs, 1H, OH), 4.20-4.00 (m, 5H, OCH₂ CHOHNCH₂ Q), 2.72(m, 2H, CH₂ N), 2.50 (s, 3H, NCH₃).

Step 3) Preparation of(-)-(S)-N-[4-[2-Hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamide

A mixture of(S)-1-[methyl(2-quinolinylmethyl)amino]-3-(4-nitrophenoxy)-2-propanol(4.60 g, 12.51 mmol) and 5% Pd/C (0.46 g) in ethanol (100 mL) in a Parrreactor was charged with H₂ (50 psi) for 3 hours. The mixture was thenfiltered through solka floc and concentrated to afford 4.0 g (95%) ofproduct which was used directly in the next step. Methanesulfonylchloride (1.08 mL, 13.95 mmol) was added dropwise to a stirring solutionof the amine (3.93 g, 11.66 mmol) and pyridine (1.89 mL, 23.36 mmol) indichloromethane (25 mL) at 0° C. The reaction mixture was warmed to 0°C. and stirred for 3 hours. The mixture was concentrated in vacuo,diluted with cold water and extracted with ethyl acetate. The organiclayer was dried over MgSO₄ and evaporated under reduced pressure toafford crude product which was purified by HPLC to afford 3.46 g (72%)of a product. [α]_(D) ²⁵ =-15.96° (CH₃ OH).

¹ H NMR (DMSO-d₆): δ9.33 (s, 1H, NHSO₂ CH₃), 8.24 (d, J=8.57 Hz, 1H,quinoline-H, 7.93 (m, 2H, Quinoline-H), 7.72 (m, 1H, quinoline-H), 7.61(d, J=8.48 Hz, 1H, quinoline-H), 7.48 (m, 1H, quinoline-H), 711 (d, 8.92Hz, 2H, Ar--H), 6.83 (d, J=8.94 Hz, 2H, Ar--H), 4.96 (bs, 1H, OH), 3.96(m, 2H, OCH₂), 3.81 (m, 3H, NCH₂ Q+CHOH), 2.86 (s, 3H, NHSO₂ CH₃), 2.48(m, 2H, CHOHCH₂ NCH₂), 2.27 (s, 3H, NCH₃).

IR (KBr): cm⁻¹ 3450 (OH), 3180 (NH).

MS (m/e): 416 (MH⁺, 75%).

Anal. Calcd. (for 0.4 NaCl adduct): C, 57.47; H, 5.74; N, 9.57. Found:C, 57.44; H, 5.28; N, 9.28.

We claim:
 1. The compounds of formula (I): ##STR12## wherein R¹ isalkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido of 6 to 10carbon atoms, perfluoroalkylsulfonamido of 1 to 6 carbon atoms,perfluoroalkylamido of 1 to 6 carbon atoms, alkylsulfone oralkylsulfoxide of 1 to 6 carbon atoms, NO₂, CN, or 1-imidazoyl; R² isstraight or branched alkyl chain of 1 to 6 carbon atoms; X is O, S, orNR³ wherein R³ is H or a straight or branched alkyl chain of 1 to 6carbon atoms; Y is CH₂ or CHOH; Het is ##STR13## wherein R⁴ is H,--NHSO₂ (C₁ to C₆ alkyl), --NHCO (C₁ to C₆ alkyl), Cl, F, Br, OCH₃, orNO₂ or the pharmaceutically acceptable salt thereof.
 2. The compoundsaccording to claim 1 of formula (II) ##STR14## wherein R¹ is NO₂ ormethylsulfonamido; Y is CH₂ or CHOH; and Het is ##STR15## wherein R⁴ isH, methylsulfonamido, Cl, F, or OCH₃ or the pharmaceutically acceptablesalt thereof.
 3. The compound according to claim 2N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamideor the pharmaceutically acceptable salt thereof.
 4. The compoundaccording to claim 2N-[4-[3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamideor the pharmaceutically acceptable salt thereof.
 5. The compoundaccording to claim 21-[methyl(2-quinolinylmethyl)amino]-3-(4-nitrophenoxy)-2-propanol or thepharmaceutically acceptable salt thereof.
 6. The compound according toclaim 2N-[2-[[[2-hydroxy-3-[4-[(methylsulfonyl)amino]phenoxy]propyl]methyl]amino]methyl]-6-quinolinyl]methanesulfonamideor the pharmaceutically acceptable salt thereof.
 7. The compoundaccording to claim 2N-[4-[3-[[(6-fluoro-2-quinolinyl)methyl]methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamideor the pharmaceutically acceptable salt thereof.
 8. The compoundaccording to claim 2N-[4-[3-[[(6-chloro-2-quinolinyl)methyl]methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamideor the pharmaceutically acceptable salt thereof.
 9. The compoundaccording to claim 2N-[4-[2-hydroxy-3-[[(6-methoxy-2-quinolinyl)methyl]methylamino]propoxy]phenyl]methanesulfonamideor the pharmaceutically acceptable salt thereof.
 10. The compoundaccording to claim 2N-[2-[[methyl[3-[4-[(methylsulfonyl)amino]phenoxy]propyl]amino]methyl]-6-quinolinyl]methanesulfonamideor the pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 2(+)-(R)-N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamideor the pharmaceutically acceptable salt thereof.
 12. The compoundaccording to claim 2(-)-(S)-N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamideor the pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition having antiarrhythmic properties which comprises aneffective amount of a compound of the formula (I) of claim 1 or itsphysiologically tolerated acid addition salt and a pharmaceuticallyacceptable carrier and diluent.
 14. A method of treating arrhythmiawhich comprises administering to a mammal suffering from cardiacarrhythmia and conditions characterized by coronary arteries vasospasman effective amount of a compound of the formula (I) of claim 1 or itspharmaceutically acceptable acid addition salt.